Cutaneous T-Cell Lymphoma
Key Points
Primary cutaneous T-cell lymphoma is a heterogeneous group of non-Hodgkin lymphomas that is responsible for two-thirds of all cutaneous lymphomas
The most common forms are mycosis fungoides, which primarily involves the skin, and Sézary syndrome, which involves the skin and blood
The etiology remains unknown, but genetic, environmental, and infectious agents have been implicated as possible risk factors
Chromosomal abnormalities, including loss at 10q and abnormalities in p15, p16, and p53 tumor suppressor genes have also been described, especially in advanced stages of the disease
In the eyelids, it usually presents with localized cutaneous patches or plaques with flaking blepharitis, and eyelid thickening that advances to skin tumors, erythroderma, and extensive node or visceral involvement
Other ophthalmic findings include conjunctival injection, episcleral infiltrates, punctate keratitis, stromal opacification and melts, retina infiltrates, vascular occlusions, and optic neuropathy
Treatment is primarily palliative with topical therapies to improve quality of life that can include BCNU (corticosteroids, nitrogen mustard, carmustine), topical bexarotene gel, imiquimod, interferon alpha, receptor-targeted cytotoxic fusion proteins, radiotherapy, total skin electron beam radiotherapy, and phototherapy
Patients with limited patch or plaque-stage disease have a 10-year disease-specific survival reported as 97% to 98%
In cases with more advanced tumor stage disease and lymph node involvement, the disease-specific survival is reduced to 42%
Primary cutaneous T-cell lymphoma (CTCL) encompasses a heterogeneous group of non-Hodgkin lymphomas (NHL), which are responsible for two-thirds of all cutaneous lymphomas. Mycosis fungoides (MF), also known as Alibert-Bazin syndrome, is the most common variant of CTCL, accounting for over half of all cases. It was first described in 1806 by the French physician Baron Jean-Louis Alibert1 as mycotic-like plaques in the early phases of the disease and mushroom-like tumors that can be seen late in the disease.2,3
While MF is the most common cutaneous lymphoma, it is still a relatively rare, extranodal, non-Hodgkin lymphoma that consists of a proliferation of helper T cells that exhibit an affinity for the epidermis.4 It most often presents in individuals aged 45 to 60 years but occasionally has been seen in children and adolescents.2,5,6,7 It is more common in black than in white or Asian patients and twice as frequent in men as in women. According to the Surveillance, Epidemiology and End Results (SEER) program of the United States National Cancer Institute, the incidence of MF is estimated at 5.6 per million persons, and this has remained constant for the past 2 decades.8
MF has been classified by its clinical presentation as a patch, plaque, or tumor.9 Patch or plaque lesions have a predilection for non-sun-exposed areas of the skin, although any area of the skin may be affected.10 They are frequently misdiagnosed as chronic contact dermatitis, atopic dermatitis, or psoriasis and may show areas of hypopigmentation or hyperpigmentation, atrophy, and petechiae.10
The behavior and prognosis of primary cutaneous lymphomas are often different from histologically similar systemic non-Hodgkin lymphomas that secondarily involve the skin so that they are classified as separate entities by the European Organization for Research and Treatment of Cancer and the World Health Organization.11,12 MF has been divided into several subtypes with slightly different clinical characteristics and different prognostic implications. Classical MF runs an indolent clinical course and usually progresses slowly over years or even decades as a patch or plaque. The skin lesions tend to occur in sun-protected areas and may progress from patches and plaques to tumors that often show ulceration.13 Regional lymph nodes and visceral organs may become involved in later stages of the disease.
In addition to the classical Alibert-Bazin type of MF, a long list of clinical and/or histologic variants have been reported. Bullous, hyperpigmented, and hypopigmented MF clinically behave in a similar fashion to that of classical MF. They are, therefore, not considered as separate entities. Folliculotropic MF and pagetoid reticulosis, on the other hand, do have distinctive clinicopathologic characteristics and, usually, are considered to be distinct variants. Folliculotropic MF is a localized form of CTCL characterized by the presence of folliculotropic infiltrates and lymphomatous changes around hair follicles and most commonly involves the head and neck.14 It occurs more often in adults but is seen occasionally in children and adolescents, and men are more often affected than women.
Lesions may present as groups of follicular papules, acneiform lesions, indurated plaques, or tumors and may be associated with alopecia.15,16 Pagetoid reticulosis is characterized by the presence of localized patches or plaques, with a proliferation of intraepidermal neoplastic T cells.11,17,18 Lesions generally present as a slowly progressive solitary psoriasiform or hyperkeratotic patch or plaque, usually localized on the extremities, and have a relatively good prognosis. A newer variant is papular mycosis fungoides characterized by the presence of papules in the absence of the usual patches and plaques. This variant has a relatively nonaggressive behavior and a good prognosis.19,20
Sézary syndrome (SS) is a variety of T-cell cutaneous lymphoma that develops most frequently in men during their fifth decade of life and progresses rapidly.3 It has an annual incidence rate of about 1/10,000,000 and represents about 3% of all cutaneous lymphomas. It affects the skin of the entire body as a scaling erythroderma and infiltration. SS is also known as red man syndrome because the skin is usually bright red. Alopecia, palmoplantar keratoderma, nail onychodystrophy, and lower eyelid ectropion may also be present. Neoplastic T cells (Sézary cells) are located in the skin, enlarged lymph nodes, and in the peripheral blood. The disease can advance to involve the liver, spleen, and bone marrow.
Etiology and Pathogenesis
The etiology of MF remains unknown, but genetic, environmental, and infectious agents have been implicated as possible risk factors in initiating lymphocyte activation.21,22 Clonal T-cell receptor gene rearrangements have been found in most cases of classic MF. Chromosomal abnormalities, including loss at 10q and abnormalities in p15, p16, and p53 tumor suppressor genes have also been described, especially in advanced stages of the disease.13,23 MF has been observed related to mature CD4+ memory cells, and a hypothesis of persistent antigen stimulation leading to a breakdown in immune surveillance and eventually malignancy has been proposed as an initial event.24
 FIGURE 129.1 A, Early manifestation of mycosis fungoides as erythematous induration of the eyelids. B, Late-stage tumorous mycosis fungoides. A, (Courtesy of Dr. Bita Esmaeli.) |
Malignant T cells in MF arise from skin-homing T cells, and the tumor microenvironment is critically involved in supporting tumor growth.25 Cytokine expression and functional variations in the immune system have been seen in the various stages of MF. Early-stage disease expresses a Th1 type helper T-cell cytokine pattern, which limits the disease to the skin. With progression to late stages, there is a shift from Th1 to a Th2 type helper T-cell profile,26,27,28,29 and this cytokine shift may promote malignant lymphocyte proliferation.25 In addition, resident skin T cells express various chemokine receptors, which are necessary for migration into the skin.30,31
SS has been linked to a wide range of chromosomal anomalies, particularly rearrangements in the 6q23-27 region that lead to alterations in the MYB proto-oncogene and the interleukin-22 receptor subunit alpha-2 gene (IL22RA2). However, the etiology remains unknown.
Clinical Presentation
The diagnosis of mycosis fungoides is usually difficult, especially in early stages, and often requires multiple biopsies for confirmation because of its clinical similarity to other conditions.32,33,34 Erythematous plaques are usually the initial manifestation, similar to other mild skin disorders such as eczema, atopic dermatitis, psoriasis, and pityriasis lichenoides (Figure 129.1A). As the disease progresses, infiltrative lesions appear, and in the late stage, tumorous lesions develop (Figure 129.1B) and metastasis to lymph nodes and distant organs may follow.
MF is more common in males at a median age at diagnosis of 55 years.35 Blacks are almost twice as likely to develop
MF compared with whites and Asians.36 In the eyelid, the disease usually presents with localized cutaneous patches and/or plaques in the early stages. More advanced stages include erythroderma and extensive node or visceral involvement. Flaking blepharitis is a common finding, followed by eyelid thickening with eyelash and eyebrow flaking. The most frequent complaints are burning, impaired vision, redness, itching, and crusting of the eyelids and eyebrows.37 Other findings include conjunctival injection; episcleral infiltrates; punctate keratitis with stromal opacification, melts, and subepithelial infiltrates; retina, choroid, and vitreous infiltrates; uveitis and vascular occlusions; and optic nerve infiltration and neuropathy.38,39,40,41,42,43,44,45,46 Nonspecific manifestations include dry eyes, cataracts, glaucoma, and peripheral nerve palsy, among others.
MF compared with whites and Asians.36 In the eyelid, the disease usually presents with localized cutaneous patches and/or plaques in the early stages. More advanced stages include erythroderma and extensive node or visceral involvement. Flaking blepharitis is a common finding, followed by eyelid thickening with eyelash and eyebrow flaking. The most frequent complaints are burning, impaired vision, redness, itching, and crusting of the eyelids and eyebrows.37 Other findings include conjunctival injection; episcleral infiltrates; punctate keratitis with stromal opacification, melts, and subepithelial infiltrates; retina, choroid, and vitreous infiltrates; uveitis and vascular occlusions; and optic nerve infiltration and neuropathy.38,39,40,41,42,43,44,45,46 Nonspecific manifestations include dry eyes, cataracts, glaucoma, and peripheral nerve palsy, among others.
The frequency of ophthalmic involvement in mycosis fungoides is not well established. Among 30 patients described by Stenson and Ramsay,47 11 (36.7%) had ophthalmologic manifestations. Most common were dry eyes (37%), ectropion (33%), and eyelid tumors (27%), with conjunctival tumors, keratitis, uveitis, and optic atrophy all reported in 10% of cases or less. Leib et al37 described 17 cases of MF, and the eyelids were the most frequently affected region (76%), characterized by seborrheic blepharoconjunctivitis, cicatricial ectropion, meibomiantitis, chalazion, and madarosis. Cook et al48 assessed 42 cases of cutaneous T-cell lymphoma and reported that ectropion was the most prevalent condition, seen in 40.4% of cases.
The disease usually follows a protracted course, through three stages: patch, plaque, and tumor. In some cases the disease may not advance to other stages,49 but up to one-third of cases it will progress to a more aggressive form with infiltration or tumors, and in some cases can develop with erythroderma.32,34,50
In SS, the cutaneous involvement is characterized by reddened, thickened, peeling, and painful skin patches, plaques, and tumors all over the body (Figure 129.2). Sézary cells are also found in the blood and lymph nodes.
 FIGURE 129.2 T-cell cutaneous lymphoma in Sézary syndrome. (Courtesy of Dr. Timothy Sullivan.) |
Differential Diagnosis
MF is easily confused with other more common skin disorders. The differential diagnosis includes eczema, psoriasis, drug reactions, atopic and contact dermatitis, pityriasis lichenoides, and other lymphomas.
Treatment
MF usually runs an indolent, uncontrollable course, and treatment is primarily palliative.32,34,50 The only treatment that can cure the disease is a bone marrow transplant, which is rarely used.51,52 When MF is confined to the skin, skin-directed therapies are preferred. These include topical BCNU (corticosteroids, nitrogen mustard, carmustine), topical bexarotene gel (retinoid), imiquimod cream, interferon alpha and other cytokines, receptor-targeted cytotoxic fusion proteins, radiotherapy, total skin electron beam radiotherapy, and phototherapy.53,54,55,56,57 However, the role of these treatments, as single-agent therapies or in combination with others, remains unclear.
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